Diabetes mellitus is associated with liver metastasis of colorectal cancer through production of biglycan-rich cancer stroma

Fujiwara‐Tani, Rina; Sasaki, Takuma; Fujii, Kenichi; Luo, Yi; Mori, Takuya; Kishi, Satoru; Mori, Shiori; Matsushima-Otsuka, Sayako; Nishiguchi, Yukiko; Goto, Kei; Kawahara, Isao; Kondoh, Masuo; Sho, Masayuki; Kuniyasu, Hiroki

doi:10.18632/oncotarget.27674

Cited by 14 publications

(14 citation statements)

References 60 publications

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“…In diabetic conditions, HMGB1 may be glycated. Furthermore, in colorectal cancer with diabetes, hemoglobin A1c levels are correlated with cancer stage and metastasis [ 17 ], and it has been reported that liver metastasis is particularly promoted in diabetes-complicated colorectal cancer [ 45 ]. Data from our small cohort of gastric cancer patients show that HMGB1 levels were correlated with primary tumor progression and distant metastasis, whereas CML-HMGB1 levels were correlated with primary tumor progression, lymph node metastasis, distant metastasis, and stage.…”

Section: Discussionmentioning

confidence: 99%

Role of Glycated High Mobility Group Box-1 in Gastric Cancer

Kishi

Nishiguchi

Honoki

et al. 2021

IJMS

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Advanced glycation end products (AGEs) are produced in response to a high-glucose environment and oxidative stress and exacerbate various diseases. Nε-(Carboxymethyl)lysine (CML) is an AGE that is produced by the glycation of lysine residues of proteins. There are a few reports on alterations in protein function due to CML modification; however, its association with cancer is not clear. We investigated the significance of CML modification in high mobility group box protein-1 (HMGB1), a cytokine that is significantly associated with cancer progression. Treatment of the gastric cancer cell lines TMK1 and MKN74 with glyoxal or glucose resulted in increased CML modification compared to untreated cells. CML-HMGB1 was modified via oxidation and more pronouncedly activated the receptor for AGE and downstream AKT and NF-κB compared to naïve HMGB1 and oxidized HMGB1. CML-HMGB1 bound with reduced affinity to DNA and histone H3, resulting in enhanced extranuclear translocation and extracellular secretion. Treatment of gastric cancer cells with CML-HMGB1 enhanced cell proliferation and invasion, sphere formation, and protection from thapsigargin-induced apoptosis, and decreased 5-FU sensitivity in comparison to HMGB1. Further, CML-HMGB1 was detected at various levels in all the 10 gastric cancer tumor specimens. HMGB1 levels correlated with primary tumor progression and distant metastasis, whereas CML-HMGB1 levels were associated with primary tumor progression, lymph node metastasis, distant metastasis, and stage. In addition, CML-HMGB1 levels correlated with oxidative stress in cancer tissues and resistance to neoadjuvant therapy. Therefore, CML modification of HMGB1 enhanced the cancer-promoting effect of HMGB1. In this study, CML-HMGB1 has been highlighted as a new therapeutic target, and analysis of the molecular structure of CML-HMGB1 is desired in the future.

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Section: Discussionmentioning

confidence: 99%

Role of Glycated High Mobility Group Box-1 in Gastric Cancer

Kishi

Nishiguchi

Honoki

et al. 2021

IJMS

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“…While biglycan is mostly known as a structural element of the ECM, more recent studies have identified critical roles for increased biglycan expression in tumor initiation and progression by playing a role as a signaling molecule in the regulation of inflammation, angiogenesis and autophagy [ 15 , 19 , 20 , 21 ]. Moreover, numerous studies have implicated biglycan in contributing to the progression of many types of tumors [ 16 , 22 ], and biglycan is considered a marker for CRC development [ 16 , 17 , 23 , 24 , 25 , 26 ]. In our immunohistochemical analyses conducted on tissues from CRC patients, high levels of biglycan expression were detected in the stroma around the CRC tissue, which is supportive of the critical role that increased biglycan expression plays in the ECM contributing to tumor progression.…”

Section: Discussionmentioning

confidence: 99%

A Necessary Role for Increased Biglycan Expression during L1-Mediated Colon Cancer Progression

Saha

Cheriyamundath

Kumar

et al. 2021

IJMS

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Aberrant activation of Wnt/β-catenin signaling and downstream β-catenin-TCF target genes is a hallmark of colorectal cancer (CRC) development. We identified the immunoglobulin-like cell adhesion receptor L1CAM (L1) as a target of β-catenin-TCF transactivation in CRC cells. Overexpression of L1 in CRC cells confers enhanced proliferation, motility, tumorigenesis, and liver metastasis, and L1 is exclusively localized at invasive areas of human CRC tissue. Several genes are induced after L1 transfection into CRC cells by a mechanism involving the L1-ezrin-NF-κB pathway. We conducted a secretomic analysis of the proteins in the culture medium of L1-overexpressing CRC cells. We detected a highly increased level of biglycan, a small leucine-rich ECM component, and a signaling molecule. We found that induction of biglycan is required for the cellular processes conferred by L1, including enhanced proliferation, motility, tumorigenesis, and liver metastasis. The suppression of endogenous biglycan levels or a point mutation in the L1 ectodomain that regulates cell–cell adhesion mediated by L1 blocked the enhanced tumorigenic properties conferred by L1. The mechanism of biglycan induction by L1 involves the L1-NF-κB pathway. Blocking NF-κB signaling in L1 expressing cells suppressed the induction of biglycan and the tumorigenic properties conferred by L1. Biglycan expression was undetectable in the normal colonic mucosa, but expressed at highly increased levels in the tumor tissue, especially in the stroma. The therapeutic strategies to target biglycan expression might provide a useful approach for CRC treatment in L1-overexpressing tumors.

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“…Immunohistochemical staining for CD133 was performed using the immunoperoxidase technique 6 with a CD133 antibody (0.5 μg/ml, Abcam). The number of positive cells was counted, and the mean value was calculated from the microscopic observation of 30 high‐power fields of view.…”

Section: Methodsmentioning

confidence: 99%

Oxidized high mobility group B‐1 enhances metastability of colorectal cancer via modification of mesenchymal stem/stromal cells

et al. 2022

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High mobility group box‐1 (HMGB1) is known to be a chemotactic factor for mesenchymal stem/stromal cells (MSCs), but the effect of post‐translational modification on its function is not clear. In this study, we hypothesized that differences in the oxidation state of HMGB1 would lead to differences in the function of MSCs in cancer. In human colorectal cancer, MSCs infiltrating into the stroma were correlated with liver metastasis and serum HMGB1. In animal models, oxidized HMGB1 mobilized three‐fold fewer MSCs to subcutaneous tumors compared with reduced HMGB1. Reduced HMGB1 inhibited the proliferation of mouse bone marrow MSCs (BM‐MSCs) and induced differentiation into osteoblasts and vascular pericytes, whereas oxidized HMGB1 promoted proliferation and increased stemness, and no differentiation was observed. When BM‐MSCs pretreated with oxidized HMGB1 were co‐cultured with syngeneic cancer cells, cell proliferation and stemness of cancer cells were increased, and tumorigenesis and drug resistance were promoted. In contrast, co‐culture with reduced HMGB1‐pretreated BM‐MSCs did not enhance stemness. In an animal orthotopic transplantation colorectal cancer model, oxidized HMGB1, but not reduced HMGB1, promoted liver metastasis with intratumoral MSC chemotaxis. Therefore, oxidized HMGB1 reprograms MSCs and promotes cancer malignancy. The oxidized HMGB1–MSC axis may be an important target for cancer therapy.

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Diabetes mellitus is associated with liver metastasis of colorectal cancer through production of biglycan-rich cancer stroma

Cited by 14 publications

References 60 publications

Role of Glycated High Mobility Group Box-1 in Gastric Cancer

Role of Glycated High Mobility Group Box-1 in Gastric Cancer

A Necessary Role for Increased Biglycan Expression during L1-Mediated Colon Cancer Progression

Oxidized high mobility group B‐1 enhances metastability of colorectal cancer via modification of mesenchymal stem/stromal cells

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